Rapid advances in the characterization of eukaryotic genomes have led to an awareness of the increasing complexity in cellular growth controls and the mechanisms by which their deregulation contributes to cancer. Signaling pathways are interconnected through multiple effectors that determine cell fate. The tumor suppressor gene p53 is one such critical effector. Loss of p53 function is found in most human cancers and can be an early or late event in the malignant process. Accumulating evidence indicates that p53 is induced by and plays a major role in determining cellular responses to a variety of pathophysiologic stresses. p53 functions importantly in determining cell fate decisions including growth arrest, replicative senescence or apoptotic cell death. The program goals are to elucidate mechanisms involved in p53 regulation and functions from novel perspectives of discoveries made within the program and to elucidate signaling pathways critical to cellular stress responses. The overall long term objectives of this research are to develop understanding of mechanisms by which p53 integrates responses to cellular stresses ranging from severe hypoxia and inflammation to the effects of genotoxic agents including many cancer therapeutics in determining cell fate decisions. This program brings together a senior group of investigators from different disciplines and with complementary expertise focused on important and novel aspects of p53 biology identified within the program. The overall significance of this research effort is that major insights gained in the investigation of cellular stress responses involving p53 offer the potential for improved therapeutic approaches to cancers, which grow and spread within a microenvironment comprised of normal cells, as well as for other pathophysiologic conditions, which activate this central mediator of cell fate decisions. In addition, an understanding of p53 function in mediating normal stem cell behavior could aid in the design of therapeutic interventions, which do not disrupt important processes important to tissue homeostasis.